Pancreatic cancer has one of the highest mortality rates of any malignancy, and the 5-year-survival rate of patients is 4%. Approximately 28,000 patients are diagnosed with pancreatic cancer each year, and nearly all patients will die of their disease (Greenlee, R. T., et al., (2001) CA Cancer J Clin, 51: 15-36). The poor prognosis of this malignancy results from the difficulty of early diagnosis and the poor response to current therapeutic methods (Greenlee, R. T., et al. (2001) CA Cancer J Clin, 51: 15-36, Klinkenbijl, J. H., et al. (1999) Ann Surg, 230: 776-82; discussion 782-4.). In particular, there are currently no identified tumor markers that allow for reliable screening at an early, potentially curative stage of the disease.
Research aimed at the elucidation of carcinogenic mechanisms has revealed a number of candidate target molecules for the development of anti-tumor agents. For example, the farnesyltransferase inhibitor (FTI) has been shown to be effective in the treatment of Ras-dependent tumors in animal models (Sun J et al., (1998) Oncogene, 16:1467-73.). This pharmaceutical agent was subsequently developed to inhibit growth signal pathways related to Ras, which is dependant on post-transcriptional farnesylation. Human clinical trials in which anti-tumor agents were applied in combination with the anti-HER2 monoclonal antibody, trastuzumab, in order to antagonize the proto-oncogene HER2/neu have succeeded in improving clinical response, and improved the overall survival rate of breast cancer patients. Tyrosine kinase inhibitor STI-571 is an inhibitor which selectively deactivates the bcr-abl fusion protein. This pharmaceutical agent was subsequently developed for the therapy of chronic myeloid leukemia, wherein the constant activation of bcr-abl tyrosine kinase plays a significant role in the transformation of white blood cells. Such pharmaceutical agents are designed to inhibit the carcinogenic activity of specific gene products (Molina M A, et al., (2000) Cancer Res, 16:4744-9). Thus, in cancer cells, gene products with promoted expression generally serve as potential targets for the development of novel anti-tumor agents. Alternatively, nucleic acid synthesis inhibitors may also be used as anti-tumor agents. For example, gemcitabine (GemzarR) is a first-line treatment of pancreatic cancer. The combination therapy of gemcitabine and paclitaxel has also been applied to treatment of pancreatic cancer.
Meanwhile, tumor angiogenesis is critically involved in the progression of tumors. It has previously been demonstrated that an effective vaccine against tumor angiogenesis could be developed according to an endothelial cell-based approach, targeting vascular endothelial growth factor receptors (VEGFRs) 1 and 2, as HLA class I molecules are not down-regulated on endothelial cells (Wada S et al., Cancer Res 2005 Jun. 1, 65(11): 4939-46; Ishizaki H et al., Clin Cancer Res 2006 Oct. 1, 12(19): 5841-9). Peptides that induce cytotoxic T lymphocytes (CTLs) specific to cells expressing VEGFR and thereby suppress tumor angiogenesis with a specific and efficient CTL response have been previously described as well (See WO/2004/024766, incorporated by reference herein).
The present invention addresses the need in the art for an improved pancreatic cancer therapy by providing a novel combination therapy for pancreatic cancer that utilizes an antigenic peptide, particularly antigenic peptides and cancer vaccines that target VEGFR2, and a chemotherapeutic agent such as gemcitabine.